Heart repolarization changes after anthracycline therapy in the children with cancer.

BACKGROUND
Anthracyclines are important components of many chemotherapeutic protocols. The present study aimed to evaluate the repolarization changes in electrocardiography (ECG) which may predict drug induced arrhythmia.


MATERIALS AND METHODS
In this cross-sectional study, the recorded ECGs were assessed for QT dispersion (QTd), QT corrected dispersion (QTcd), T peak to Tend dispersion (TPed), and P dispersion (Pd) in 12 ECG leads. The demographic information, including sex, age, and duration of drug consumption, were recorded, as well.


RESULTS
In this study, 112 patients, including 58 females (52%) and 54 males (48%) with the mean age of 8.7±4.5 years, as the case group were compared with 43 children, including 17 males (40%) and 26 females (60%), in the control group. Most of our patients (88%) had received usual doses of anthracyclines; i.e., 330 mg/m2. QT dispersion of the patients and the controls was 0.054±0.02 and 0.05± 0.02 seconds, respectively. No significant difference was found between the patients and the controls regarding corrected QT dispersion (P> 0.05). However, P dispersion time had increased in the patients' group. Our study showed that the duration of anthracyclines therapy did not cause any significant increase in ventricular re-polarization parameters.


CONCLUSION
Anthracyclines may show their cardiac toxicity through increasing P dispersion.


Introduction
Anthracyclines are commonly used antineoplastic drugs. However, their clinical utility is tempered by a dose-dependent risk of cardiotoxicity and congestive heart failure (1,2). Recent research has focused on early monitoring and risk stratification to identify patients that are 'at risk' for cardiotoxicity. Dose reduction, using biochemical markers or less cardiotoxic anthracycline analogues and prophylactic consumption of dexrazoxane are strategies which could be reduce anthracycline associated morbidity (3,4). Cardiac complications due to anthracyclines may develop several years after chemotherapy and are considered as a major cause morbidity and mortality in cancer patients after secondary malignancies and recurrence (5,6). The mechanism of cardiac toxicity of these drugs has not been fully characterized (7,8). Some risk factors, such as age, dose, female gender, and radiation therapy, are known; however, the relative risks of many diseases, such as diabetes and hypertension, have not been well studied. Mechanisms of anthracyclines on leukemia cells may intercalate into the DNA of replicating cells, leading to DNA fragmentation, inhibition of polymerases, and finally decrease in DNA, RNA, and protein synthesis (9,10). Although the exact mechanisms of anthracyclines damage to heart myocytes is unknown, there are several hypotheses (11). Elevations in serum cardiac troponins (T and I), representing a potential marker of damage, are associated with damage to heart cells (12).
Anthracyclines cardio toxicities may occur in three stages: acute, sub-acute, and late (chronic). Acute and sub-acute toxicities may present with an abnormal electrocardiogram (ECG), ventricular and supra ventricular arrhythmias, ventricular dysfunction, and pericarditis-myocarditis syndrome (13)(14)(15)(16). More than 30% decrease in QRS wave voltage may be an early evidence of cardiomyopathy in the patients receiving adriamycines (17,18). The QT interval is a clinically important electrocardiographic measurement. In standard ECG, the QT interval shows the time between depolarization and end of repolarization. The usual method of ventricular repolarization measurement is based on the QT interval in lead 2 or in the lead which has the largest T wave (19). The QT should be corrected for the heart rate (QTc). Prolongation of the QTc (>440 ms) is equal to prolonged repolarization period of the ventricles which may result in fatal arrhythmias, including torsade de points, and a high mortality rate (20). QT dispersion is an indicator of general repolarization abnormality which may reflect the regional differences in ventricular recovery time and has been linked to the development of malignant arrhythmia in different cardiac diseases (21,22). Depolarization abnormality may be reported sometimes in other condition such as children with syncope (23). The normal range for QTd is 40-50 mili seconds and QTd of more than 65 milli seconds may increase the risk of arrhythmia and sudden death. The other criteria of repolarization are T peak to T end interval (TPE) and dispersion. TPE provides an index of maximum dispersion of repolarization and is an indicator of the transmural dispersion of the repolarization in different regions of the ventricular myocardium (24). Recent studies have used the P wave dispersion as a parameter for predicting atrial arrhythmias in several disorders (25)(26)(27).
The health related quality of life (QOL) has been accepted as an effective aspect of the patients' treatment, especially in chronic diseases, such as cancers (17). Cumulative dose of anthracyclines is a major risk factor for drug induced cardiac complications. Thus, we performed this study in order to determine the repolarization changes after anthracyclines chemotherapy in children and probable practical use of these parameters for early diagnosis of anthracyclines cardiac toxicities.

Materials and Methods
The present cross-sectional study was conducted one 112 patients less than 18 years old who were diagnosed as a case of childhood cancer and were under treatment with anthracyclines. All the patients with congenital heart diseases, history of radiotherapy, overt pulmonary or renal insufficiency, and congenital arrhythmia were excluded from the study. Written informed consent was obtained from the patients or their parents. In addition, the study was approved by the Ethics Committee of Shiraz University of Medical Sciences, Shiraz, Iran. The measured ECG parameters, including QT dispersion, P dispersion, QTc dispersion, and TPE dispersion, were compared between the case and control groups. For all the study participants, their physical examination and medical history were recorded by a physician and a 12 lead digital standard ECG was obtained from the case and control groups. All the recordings were made at a paper speed of 25 mm/s with a digital electrocardiogram machine (Alicia Diagnostics, Sanford, FL, USA). The digitally recorded electrocardiogram tracings were evaluated using a digital clipper in Corel Photo Paint v.13 software (Ottawa, Canada). Magnification of the electrocardiogram made a fine determination of the measurement points. It should be noted that the electrocardiogram was interpreted by two cardiologists separately. Each measurement was repeated for 3 times and the mean values were calculated, as well. The QT interval was measured from the beginning of the QRs complex to the termination of the T wave (defined as the return to the isoelectric line). Bazett's formula was used to calculate the QTc: QTc= QT interval(s)/ (√R-R interval) (sec). The onset of the P wave was defined as the junction between the isoelectric line and the start of the P wave deflection. Besides, the offset of the P wave was defined as the point where the final deflection of the P wave crossed the isoelectric line. The leads with unclear onset or offset of the P wave were excluded from the study. Then, the P wave dispersion was calculated according to its definition as the difference between P maximum duration and P minimum duration in the 12 lead ECG. The T-peaked to T-end interval and T-peaked to T-end dispersion (defined as the difference between the maximum and minimum T-peaked to Tend interval in precordial leads V1 to V6 during a single beat ) were also measured. The T-peak to Tend was measured in each precordial lead and obtained from the difference between QT interval and QT peak interval, measured from the beginning of the QRS up to the peak of the T-wave. A control group was selected from children with normal heart exam, no pathologic finding in echocardiography and normal ECG. The demographic data, including age and sex, and anthracyclines dose information, including <200 mg/m2, 200-300 mg/m2, and > 300 mg/m2, were recorded, as well. We also investigated the relationship between ECG findings and duration of anthracyclines treatment (less than one month, 1-6 months, and more than 6 months). The control group and these three groups of patients were matched for age. The measured ECG parameters, including QT dispersion, P dispersion, QTc dispersion, and TPE dispersion, were compared in both study groups.

Statistical analysis
Statistical analysis of the obtained data was performed under the supervision of a statistician using the SPSS statistical software (v. 15) (Chicago, IL, USA). ANOVA, T test, Pearson correlation, and linear regression were used in order to analyze the data. Besides, P value <0.05 was considered as statistically significant.

Results
The current study was conducted on 112 patients, including 58 females (52%) and 54 males (48%) with the mean age of 8.7± 4.5years, who received anthracyclines for chemotherapy and 43 children, including 17 males (40%) and 26 females (60%) with the mean age of 8.6± 4.3, in the control group (p=0.8). Comparison of QT dispersion and QTc dispersion between the patients and the controls showed no statistically significant difference; however, P dispersion and TPE dispersion values were different between the two groups (Table I). Moreover, the study results revealed an increase in P dispersion (0.02 second) and a decrease in TPE (0.09 second) in the drug receiving group.

The effect of treatment duration:
According to the duration of the treatment, the case group was divided into 3 groups including the patients with less than one month (31 cases), more than one month to 6 months (33 patients), and more than 6 months of treatment (48 cases). According to the study findings, the QT dispersion in the patients who had received anthracyclines for less than a month was 0.048±0.017 which was significantly longer from the 1-to 6-month group (0.062±0.023) (P=0.025). Furthermore, the P dispersion was higher in the 6-to 12-month group compared to the group which had not received any treatment (0.281±0.048 seconds versus 0.254±0.026, P=0.013).
The results also showed that the TPE dispersion in the patients who had been treated for less than a month was 0.041 ± 0.061 which was significantly different from the control group (0.051±0.016). The comparisons of the patients with less than one month, one to six months, and more than 6 months of treatment regarding the electrocardiographic parameters are presented in Table II.

Anthracyclines dosage:
The three patient groups which had received less than 200 mg /m2 (n=63), 200 to 300 mg /m2 (n=30), and more than 300 mg /m2 (n=16) anthracycline and the control group were compared regarding the cumulative dose (mg /m2 of body surface area). According to the results, P dispersion was prolonged by increasing the dosage beyond 200mg per square meter. The drug dosage did not have any significant effect on QT dispersion (p=0.42), QTc dispersion (p=0.59), and TPE dispersion (p=0.4).

Discussion
This non-invasive study aimed to assess heart repolarization after anthracyclines treatment based on the measurement of QT dispersion, P dispersion, QTc dispersion, and TPE dispersion. First, the overall effect of these drugs on the heart was evaluated regardless of other factors, including age, sex, and drugs.
The study by Larsen and colleagues indicated that QTc prolongation, increased supraventricular, and ventricular tachycardia might occur in the patients on anthracyclines compared to the normal group (P<0.001). According to this study, no significant difference was found between the case and the control group regarding QT dispersion and QTc dispersion (p>0.05) (28). In our study, the P dispersion of the drug treated group had increased compared to the control group (0.02 seconds). The researchers could find no studies about this variable after treatment with anthracyclines chemotherapy. A study by Senen and colleagues revealed that P dispersion was higher in the patients with dilated cardiomyopathy in comparison to the normal group (29 showed that the QTc dispersion had a significant increase in the cases compared to the control group; however, this finding was not confirmed in Qt dispersion. In that study, the cumulative dose of anthracyclines was not involved in the increases of QTc dispersion and QT dispersion (31) which is in line with the results of the present study.
As shown in the current as well as the previous studies, repolarization factors are independent of gender 31. In the present study, the effect of treatment duration on ventricular repolarization factors was not statistically significant, which might be due to the short follow-up period. In fact, about 57% of our patients were evaluated for less than 6 months. In some studies, this effect was detected in more prolonged follow-up periods (28)(29)(30). Finally, our study findings showed no statistically significant correlation between the amount of drug as well as treatment duration and ECG parameters. Conclusion: Anthracyclines can show their cardiotoxicity via an increase in P dispersion. The P dispersion is the earliest and consistent factor which is not affected by the gender of the patients, but has linear correlation with age.